Critical genomic regulation mediated by Enhancer of Polycomb.

Enhancer of Polycomb (EPC) was first identified for its contributions to development in Drosophila and was soon-thereafter purified as a subunit of the NuA4/TIP60 acetyltransferase complex. Since then, EPC has often been left in the shadows as an essential, yet non-catalytic subunit of NuA4/TIP60; however, its deep conservation and disease association make clear that it warrants additional attention. In fact, recent studies in yeast demonstrated that its Enhancer of Polycomb, Epl1, was just as important for gene expression and acetylation as is the catalytic subunit of NuA4. Despite its conservation, studies of EPC have often remained siloed between organisms. Here, our goal is to provide a cohesive view of the current state of the EPC literature as it stands among the major model organisms in which it has been studied. EPC is involved in multiple processes, beginning with its cardinal role in regulating global and targeted histone acetylation. EPC also frequently serves as an important interaction partner in these basic cellular functions, as well as in multicellular development, such as in hematopoiesis and skeletal muscle differentiation, and in human disease. Taken together, a unifying theme from these studies highlights EPC as a critical genomic regulator.

Chromatin Regulation by the NuA4 Acetyltransferase Complex Is Mediated by Essential Interactions Between Enhancer of Polycomb (Epl1) and Esa1.

Enzymes that modify and remodel chromatin act in broadly conserved macromolecular complexes. One key modification is the dynamic acetylation of histones and other chromatin proteins by opposing activities of acetyltransferase and deacetylase complexes. Among acetyltransferases, the NuA4 complex containing Tip60 or its Saccharomyces cerevisiae ortholog Esa1 is of particular significance because of its roles in crucial genomic processes including DNA damage repair and transcription. The catalytic subunit Esa1 is essential, as are five noncatalytic NuA4 subunits. We found that of the noncatalytic subunits, deletion of Enhancer of polycomb (Epl1), but not the others, can be bypassed by loss of a major deacetylase complex, a property shared by Esa1 Noncatalytic complex subunits can be critical for complex assembly, stability, genomic targeting, substrate specificity, and regulation. Understanding the essential role of Epl1 has been previously limited, a limitation now overcome by the discovery of its bypass suppression. Here, we present a comprehensive in vivo study of Epl1 using the powerful tool of suppression combined with transcriptional and mutational analyses. Our results highlight functional parallels between Epl1 and Esa1 and further illustrate that the structural role of Epl1 is important for promotion of Esa1 activity. This conclusion is strengthened by our dissection of Epl1 domains required in vivo for interaction with specific NuA4 subunits, histone acetylation, and chromatin targeting. These results provide new insights for the conserved, essential nature of Epl1 and its homologs, such as EPC1/2 in humans, which is frequently altered in cancers.